Roughly 20 ICRs maintain parent-specific DNA methylation throughout life and across all tissues in mouse and human genomes, and control the mono-allelic and parent-of-origin expression of approximately 150 imprinted genes ( Schulz et al., 2008 Tucci et al., 2019).ĭNA methylation-based genome-wide screens have led to the conclusion that all life-long ICRs have probably been discovered ( Proudhon et al., 2012 Xie et al., 2012). However, some gDMRs are protected through sequence- and DNA methylation-specific recruitment of the KRAB-associated protein 1 (KAP1) complex ( Li et al., 2008 Quenneville et al., 2011 Takahashi et al., 2019) and become fixed as imprinting control regions (ICRs). After fertilization, the vast majority of gDMRs are lost during the epigenetic reprogramming that the embryonic genome undergoes ( Seah and Messerschmidt, 2018). In mammals, genomic imprinting arises from sex-specific patterning of DNA methylation during gametogenesis, which generates thousands of germline differentially methylated regions (gDMRs) between the oocyte and the spermatozoa. Genomic imprinting is the process by which a subset of genes is expressed from only one copy in a manner determined by the parental origin. This study demonstrates that precise imprinted gene dosage is essential for vital physiological functions at the transition from intra- to extra-uterine life, here the adaptation to oral feeding and optimized body weight gain. Consequently, only half of Zdbf2-KO pups survived the first days after birth and those surviving were smaller. We further found that Zdbf2-KO neonates failed to fully activate hypothalamic circuits that stimulate appetite, and suffered milk deprivation and diminished circulating Insulin Growth Factor 1 (IGF-1). Here, using mouse models of loss, gain and parental inversion of expression, we report that the paternally expressed Zdbf2 gene controls neonatal growth in mice, in a dose-sensitive but parent-of-origin-independent manner. While long recognized for their role in embryonic development, imprinted genes have recently emerged as important modulators of postnatal physiology, notably through hypothalamus-driven functions. Genomic imprinting refers to the mono-allelic and parent-specific expression of a subset of genes.
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